# A Precision Medicine for Alcohol-Associated Liver Disease

> **NIH NIH UT2** · GENETOBE INC. · 2024 · $982,659

## Abstract

ABSTRACT
The goal of this study is to develop an RNAi-based genetic precision medicine to treat alcohol associated liver
disease (AALD). AALD is a devastating health problem worldwide, accounts for the majority of alcohol-related
mortality globally and is the second most indication for liver transplantation in the US. The current medical
management for AALD remains limited, and no proven pathobiology-driven pharmacotherapy is available. There
is thus an urgent need to identify novel targets and develop promising therapies for both prevention and treatment
for AALD. Recent genome-wide association studies (GWAS) has identified that a single nucleotide polymorphism
(SNP rs738409 C>G, or amino acid alteration at position 148 I>M) in the patatin-like phospholipase domain
containing 3 (PNPLA3) gene is the single largest genetic risk factor contributing to the progression of AALD to
advanced liver perturbations including liver cancer. The PNPLA3 148 I>M polymorphism is the molecular reason
why this subset of AALD patients develop severe liver injuries. Mechanistic studies have revealed that
overexpression of the mutant PNPLA3 (the 148M isoform) is underlying both liver steatosis and fibrosis and
inflammation by interrupting hepatic triglyceride metabolism. Our creation of a humanized PNPLA3148M mouse
model successfully recapitulates the AALD phenotypes and has corroborated the aforementioned mechanism.
We hypothesize that transcriptional downregulation of the PNPLA3148M isoform is a cause-targeting strategy for
the treatment of AALD with the PNPLA3148M allele. To this end, we pioneered the development and have issued
patents for a precision allele-specific small interfering RNA (siRNA) that possesses excellent specificity for the
PNPLA3148M isoform compared to its wild-type counterpart. We further discovered two more modified
oligonucleotides which significantly improved the medicinal chemistry specifications of our therapeutic lead.
Administration of our lead siRNA to the liver of the humanized PNPLA3148M model fed an ethanol-containing diet
significantly reduced the PNPLA3148M expression as well as hepatic steatosis, inflammation and fibrosis. We also
demonstrated that delivering our siRNA into the humanized PNPLA3148M model with the N-Acetylgalactosamine
(GalNAc)-conjugation, a well-established liver-specific drug delivery strategy, effectively knocked down hepatic
hPNPLA3148M mRNA and ameliorated the liver histology. With this success, we propose to advance our drug
candidate development by focusing on an Investigational New Drug (IND) application to the FDA. Specifically,
we aim: 1) to define the best drug candidate of our hPNPLA3148M-targeting, GalNAc-conjugated oligonucleotides
(Phase I); 2) to collect IND-enabling quality assurance and safety data in rodents and non-human primates
(Phase II). We expect that via this study, we will develop the first genetic medicine for AALD treatment, which
could also serve as a new prototype for drug developmen...

## Key facts

- **NIH application ID:** 10932948
- **Project number:** 5UT2AA031151-02
- **Recipient organization:** GENETOBE INC.
- **Principal Investigator:** Charles Larry Bisgaier
- **Activity code:** UT2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $982,659
- **Award type:** 5
- **Project period:** 2023-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932948

## Citation

> US National Institutes of Health, RePORTER application 10932948, A Precision Medicine for Alcohol-Associated Liver Disease (5UT2AA031151-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932948. Licensed CC0.

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